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Altered Ten Eleven Translocation Methylcytosine Dioxygenase Expression and DNA Hydroxymethylation in a Mouse Model of Prostate Cancer [RNA-seq]

ABSTRACT: Background: DNA hydroxymethylation (5hmC) is known to be altered in human prostate cancer. An animal model is required to study the functional roles of the Ten Eleven Translocation (TET) DNA dioxygenases and the 5hmC modification in prostate cancer development and progression. Methods: We characterized Tet expression, global genomic 5hmC, and genome-wide 5hmC patterns, and the transcriptome, in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) autochthonous model of prostate cancer. Results: We observed increased mRNA and protein expression of Tet1 in TRAMP samples, as compared to normal mouse prostate. Additionally, we found minimal expression of Tet2 mRNA overall, and Tet3 mRNA levels appeared similar in both sample types. However, TRAMP tumors expressed what appeared to be the inactive form of Tet3, versus the active form expressed in normal prostates. TRAMP tumors displayed global genomic hypohydroxymethylation (i.e., loss of 5hmC), and genome-wide analysis revealed widespread hypohydroxymethylation was interspersed with regions of locus specific hyperhydroxymethylation (i.e., increased 5hmC). The differentially hydroxymethylated regions correlated with altered gene expression, and pathway analyses indicated that these genes often participate in oncogenic pathways.Conclusions: Tet expression and 5hmC patterns are altered in the TRAMP model and closely match what has been observed in human prostate cancer, suggesting that TRAMP is a suitable model to study the role of Tets and 5hmC in prostate cancer development and progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE279077 | GEO | 2025/03/21

REPOSITORIES: GEO

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Altered Ten Eleven Translocation Methylcytosine Dioxygenase Expression and DNA Hydroxymethylation in a Mouse Model of Prostate Cancer [hMeDIP-seq]

Project description:Background: DNA hydroxymethylation (5hmC) is known to be altered in human prostate cancer. An animal model is required to study the functional roles of the Ten Eleven Translocation (TET) DNA dioxygenases and the 5hmC modification in prostate cancer development and progression. Methods: We characterized Tet expression, global genomic 5hmC, and genome-wide 5hmC patterns, and the transcriptome, in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) autochthonous model of prostate cancer. Results: We observed increased mRNA and protein expression of Tet1 in TRAMP samples, as compared to normal mouse prostate. Additionally, we found minimal expression of Tet2 mRNA overall, and Tet3 mRNA levels appeared similar in both sample types. However, TRAMP tumors expressed what appeared to be the inactive form of Tet3, versus the active form expressed in normal prostates. TRAMP tumors displayed global genomic hypohydroxymethylation (i.e., loss of 5hmC), and genome-wide analysis revealed widespread hypohydroxymethylation was interspersed with regions of locus specific hyperhydroxymethylation (i.e., increased 5hmC). The differentially hydroxymethylated regions correlated with altered gene expression, and pathway analyses indicated that these genes often participate in oncogenic pathways.Conclusions: Tet expression and 5hmC patterns are altered in the TRAMP model and closely match what has been observed in human prostate cancer, suggesting that TRAMP is a suitable model to study the role of Tets and 5hmC in prostate cancer development and progression.

2025-03-21 | GSE279076 | GEO

Rest recruits neuronal Tet3 to induce chromatin remodeling and gene expression

Project description:Ten-eleven translocation (Tet) hydroxylases (Tet1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling Tet activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal Tet3 isoform lacking a DNA binding domain is targeted to the DNA. To identify factors binding to Tet3 we screened for proteins that co-precipitate with Tet3 from mouse retina and identified the transcriptional repressor Rest as a highly enriched Tet3-specific interactor. Rest was able to enhance Tet3 hydroxylase activity after co-expression and overexpression of Tet3 activated transcription of Rest-target genes. Moreover, we found that Tet3 also interacts with Nsd3 and two other H3K36 methyltransferases and is able to induce H3K36 trimethylation. We propose a mechanism for transcriptional activation in neurons that involves Rest-guided targeting of Tet3 to the DNA for directed 5hmC-generation and Nsd3-mediated H3K36 trimethylation.

2015-04-02 | PXD001857 | Pride

Control of 5mC and 5hmC by TET dioxygenases in human embryonic carcinoma cells [MBD-Seq]

Project description:The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remains largely unknown. We depleted TET1, TET2, and TET3 by siRNA in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC and 5hmC patterns. TET1 depletion yielded widespread reduction of 5hmC, while depletion of TET2 and TET3 reduced 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3-depletion also caused increased 5hmC, suggesting they play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion resulted in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function was highly specific to chromatin environment: 5hmC maintenance by all TETs occurred at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting the TETs normally promote 5hmC at these loci, and all three TETs are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes. These results provide novel insight into the division of labor among TET proteins and reveal an important connection of TET activity with chromatin landscape and gene expression. Methylation and hydroxymethylation profiling by affinity-based high throughput sequencing

2014-06-14 | E-GEOD-51902 | biostudies-arrayexpress

Control of 5mC and 5hmC by TET dioxygenases in human embryonic carcinoma cells [Microarray]

Project description:The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remains largely unknown. We depleted TET1, TET2, and TET3 by siRNA in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC and 5hmC patterns. TET1 depletion yielded widespread reduction of 5hmC, while depletion of TET2 and TET3 reduced 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3-depletion also caused increased 5hmC, suggesting they play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion resulted in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function was highly specific to chromatin environment: 5hmC maintenance by all TETs occurred at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting the TETs normally promote 5hmC at these loci, and all three TETs are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes. These results provide novel insight into the division of labor among TET proteins and reveal an important connection of TET activity with chromatin landscape and gene expression. Affymetrix gene expression Human ST1.0 microarray of NCCIT human embryonic carcinoma cells (4 samples in duplicate).

2014-06-14 | E-GEOD-51901 | biostudies-arrayexpress

Tet proteins regulate differentiation potential across retinal cell types

Project description:Tet enzymes are epigenetic modifiers that impact gene expression via 5mC to 5hmC oxidation; 5hmC generation is known to induce chromatin remodeling and promote transcriptional accessibility and therefore gene expression. Previous work demonstrated the requirement for Tet and 5hmC in early retinogenesis–revealing that Tet-null(tet2-/-;tet3-/-) zebrafish exhibit extensive retinal defects. Here, we leveraged scRNAseq technologies to better understand cell type-specific deficits and molecular signatures underlying the tet2-/-;tet3-/- phenotype across differentiation stages. Our results revealed phenotypes in developing tet2-/-;tet3-/- retinae including delayed specification of several retinal cell types, reduced maturity across late-stage tet2-/-;tet3-/- cones, expansions of immature subpopulations of both horizontal and bipolar cells, and altered biases of bipolar cell subtype fates at late differentiation stages. Together, these data support Tet proteins as regulators of cell specification, lineage fate commitment, and terminal differentiation. This study enables a better understanding of how Tet proteins impact the differentiation of many unique yet interacting cell types in a cellularly complex neuronal tissue.

2025-01-31 | GSE283588 | GEO

Control of 5mC and 5hmC by TET dioxygenases in human embryonic carcinoma cells [MBD-Seq]

2014-06-14 | GSE51902 | GEO

Control of 5mC and 5hmC by TET dioxygenases in human embryonic carcinoma cells [Microarray]

2014-06-14 | GSE51901 | GEO

Active DNA demethylation is upstream of rod photoreceptor fate determination and required for retinal development [Human RNA-Seq]

Project description:The goal of this study is to investigate the role of TET enzyme-mediated DNA demethylation on retinal development and cell fate specification. We utilized an allelic series of TET enzyme retinal conditional mouse mutants using the Chx10-Cre-GFP transgene, removing the TET enzymes from retinal progenitor cells. We observe that inhibition of DNA demethylation results in abnormal retinal development and a loss of visual function. As human retinoblastoma displays reduced TET3 protein expression and a reduction in 5hmC similar to our TET mutant models, we compare the RNA expression changes across human retinoblastoma and TET mutant retinas to identify common pathways that are altered when 5hmC is lost.

2025-03-01 | GSE288097 | GEO

Methylation arrays elucidate 5mC and 5hmC levels of human glioblastoma cell line LN229 upon restoration of TET3 expression.

Project description:DNA hydroxymethylation is frequently lost in glioblastoma. We hypothesized that reduced 5hmC levels might be related to the impaired expression of TET proteins in brain tumors. In this study we performed a genome-wide methylation analysis of LN229 cells stably transfected with scramble or TET3 overexpressing vectors. TET3 overexpression partially restored the genome-wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines.

2018-03-03 | E-MTAB-6001 | biostudies-arrayexpress

Cross-species analysis of genome-wide regulatory networks identifies a synergistic dependency between FOXM1 and CENPF that drives prostate cancer malignancy

Project description:Analysis of the transcriptome of mouse models of prostate cancer to assemble a mouse prostate cancer interactome. To assemble the mouse prostate cancer interactome, we collected 13 distinct mice or genetically-engineered mouse models (GEMMs), which together represent the full spectrum of prostate cancer phenotypes including: normal epithelium (i.e., wild-type), low-grade PIN (i.e., Nkx3.1 and APT), high-grade PIN and adenocarcinoma (i.e., APT-P; APC; Myc; NP; Erg-P; and NP53), castration-resistant prostate cancer (i.e., NP-AI), and metastatic prostate cancer (i.e., NPB; NPK; and TRAMP). To further enhance the heterogeneity afforded by this diversity of mouse models, we pharmacologically perturbed each GEMM using 13 different drugs (or appropriate vehicle). The resulting mouse prostate tissue/tumor dataset encompassed 384 expression profiles

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